Mechanism of the stimulation of insulin release in vitro by HB 699, a benzoic acid derivative similar to the non-sulphonylurea moiety of glibenclamide

1 Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property.2 At a non-stimulatory concentration of glucose (3mM), 1-adamantanamine (1 mM) reversibly inhibited`6Rb efflux from islet cells, depolarized the P-cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2" abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux.3 At a stimulatory concentration of glucose (10 mM), 1-adamantanamine reversibly increased '8Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose-dependent, with a threshold concentration of 1O iM for stimulation of release. 4 2-Adamantanamine was as potent as l-adamantanamine. In contrast, substitution of the amino group by a carboxyl group (l-adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1-adamantanol) suppressed it.

Section: Effects Ofvarious Adamantane Derivativessupporting

confidence: 48%

Section: Effects Ofvarious Adamantane Derivativesmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adamantane derivatives: a new class of insulin secretagogues

Garrino¹,

Henquin

1987

“…The compound HB699, which is similar to the non-sulphonylurea moiety of glibenclamide, was shown to be slightly less effective than glibenclamide itself but much more potent than tolbutamide. Garrino et al (1985) demonstrated that HB699 depolarized B-cells by decreasing K+ permeability and induced insulin release. They found that HB699 was much less potent than glibenclamide and only slightly more potent than tolbutamide.…”

Section: Discussionmentioning

confidence: 98%

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Sturgess

Kozlowski

Carrington

et al. 1988

166

113

1 The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp methods in an insulinsecreting cell line derived from a rat islet cell tumour. 2 Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2-5 fold. The concentrations of tolbutamide and glibenclamide giving half-maximum effects on insulin secretion were approximately 40pM and 0.2pm, respectively. 3 Diazoxide (0.6-1.0mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20mM), it produced inhibition. Tolbutamide-induced release was also inhibited by diazoxide. 4 Tolbutamide, glibenclamide, HB699 and HB985 reduced the open-state probability of the ATP-K+ channel in a dose-dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5 In whole cell recording, in which the total ATP-sensitive K+ conductance of the cell could be measured, dose-inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17pM and 27nm, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6 Diazoxide (0.6mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 pM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7 Neither tolbutamide (1.0mM) nor glibenclamide (10 M) altered the open-state probability of the Ca2 + -activated K+ channel or the Ca2 + -activated non-selective cation channel which are present in this cell line. 8 It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP-K+ channel or a protein closely associated with this channel.

“…Similarly, Garrino et al (1985) found that 1O-7IM glibenclamide reduced 86Rb efflux and increased insulin release from mouse islets perifused with a medium containing 3 mm glucose, although no attempt was made in that study to establish a threshold concentration for the sulphonylurea. Commonly, authors have tended to use higher concentrations of glibenclamide in their studies.…”

Section: Conscious Rat Studiesmentioning

confidence: 99%

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat

Buckingham

Hamilton

Howlett

et al. 1989

117

In rat isolated thoracic aortic rings pre‐contracted with noradrenaline (10−6 m), cromakalim (3 × 10−7‐3 × 10−5 m) produced concentration‐related relaxation. This effect was progressively inhibited by increasing concentrations of the anti‐diabetic sulphonylurea drug, glibenclamide (10−6‐10−5 m). In rat isolated portal veins, cromakalim (3 × 10−8‐10−6 m) produced concentration‐related inhibition of the spontaneous contractive activity and glibenclamide (3 × 10−7‐3 × 10−6 m) prevented this inhibitory action in a concentration‐dependent manner. In both rat aortic rings and portal veins, cromakalim (10−5 m) stimulated 86Rb efflux. Prior exposure to glibenclamide (10−7‐10−6 m) produced a concentration‐related inhibition of this response. In conscious rats, cromakalim, 0.075 mg kg−1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg−1). In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg−1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg−1, given by the intravenous route. The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP‐sensitive K+ channel of the pancreatic β‐cell.